Fc-bridged immune cell activation and its role in infectious diseases and autoimmune diseases

Abstract Immunoglobulin G (IgG) is critical to both humoral and cellular immunity. Conventionally, protective functions of IgG against infection and cancer require utilization of both its Fab and Fc domains. IgG Fab binds specific antigen and Fc engages complement or various Fcγ receptors (FcγRs) expressed on immune cells. We recently discovered that the IgG Fc domain alone can play a critical role in the immune cell’s recognition and elimination of certain pathogens, in vitro and in vivo, without the need for the Fab domain of IgG. Many human pathogens, such as herpes simplex virus 1 (HSV1), human cytomegalovirus (HCMV), and Staphylococcus aureus (S.A), express proteins capable of binding IgG Fc (called FcBP hereafter to differentiate from FcγR). FcBPs bind the IgG Fc domain at a site that is distinct and non-overlapping with the site bound by FcγRs. We have demonstrated that a trimeric FcBP-Fc-FcγR complex is formed when the FcγR-bearing immune cell with its bound IgG recognizes, binds to and is therefore activated by the pathogen expressing FcBP. The IgG Fc domain serves as a bridge between the FcγR positive immune cells and the FcBP-bearing pathogens. We have named this process “Fc-bridged cell-mediated cytotoxicity”, or FcBCC. We have demonstrated that FcBCC (1) results in the in vivo elimination of HSV1; (2) prevents fatal HSV1 infection; (3) depends on IgGFc and the FcγR+ NK cell, but (4) does not depend on IgG Fab. Thus IgG Fc alone is necessary and sufficient for engaging both the pathogens and the FcγR-bearing immune effector cells in FcBCC. Other than infectious diseases, results showing FcBCC in some autoimmune diseases will also be presented. Research in my lab is supported by Southern Medical University startup fund.